(2024) 22:323
Wu et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03526-5

BMC Medicine

RESEARCH

Open Access

Unraveling the causality
between gastroesophageal reflux disease
and increased cancer risk: evidence from the UK
Biobank and GWAS consortia
Gujie Wu1,2†, Yaqiong Liu3†, Dong Ning4†, Mengnan Zhao1, Xiaoqing Li2, Lu Chang5, Qili Hu6, Yao Li6,
Lin Cheng3* and Yiwei Huang1*

Abstract
Background Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach
contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked
this relationship.
Methods This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD
and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancerrelated data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single
nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods suchas inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding
factors.
Results GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known
risk factors—including smoking, alcohol consumption, major depression, and body mass index (BMI)—these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer
was (OR, 1.23; 95% CI: 1.14–1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03–1.36), for lung squamouscell carcinoma was (OR, 1.35; 95% CI: 1.19–1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI:
1.22–2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23–5.37). Mediation
analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks.
Conclusions This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer
prevention strategies.
†

Gujie Wu, Yaqiong Liu and Dong Ning contributed equally to this work.

*Correspondence:
Lin Cheng
L.Cheng1@nuigalway.ie
Yiwei Huang
huang.yiwei@zs-hospital.sh.cn
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Wu et al. BMC Medicine(2024) 22:323

Page 2 of 13

Keywords Gastroesophageal reflux disease, Cancer risk, Mendelian randomization, Genome-wide association
studies, Lifestyle factors

Background
Gastroesophageal reflux disease (GERD) is a chronic gastrointestinal disorder characterized by the backflow of
stomach contents into the esophagus, affecting millions
of people globally [1]. This condition leads to symptoms
such as heartburn, acid regurgitation, and chest pain,
which significantly impair quality of life by causing sleep
disturbances, reduced work productivity, and limitations
in daily activities [2]. Currently, up to 20% of individuals in Western populations experience GERD symptoms
on a weekly basis, and the rising trend of GERD has garnered increasing attention [1, 2].
Recent epidemiological research has identified a potential link between GERD and an increased risk of multiple
cancers [3–7]. These associations may be due to the damaging effects of gastric acid and bile on mucosal surfaces
beyond the esophagus, suggesting a need for a thoroughinvestigation into GERD’s broader oncogenic potential[8]. However, existing observational studies, while highlighting a potential link, have failed to definitively establish a causal relationship between GERD and cancer. Thisgap is partly attributable to confounding factors suchas smoking, alcohol use, obesity, and major depression,
which are known risk factors for both GERD and various
cancers [9]. Therefore, determining the causal relationship between GERD and cancer requires a methodology
capable of addressing these complexities [10].
Mendelian randomization (MR) offers a robust method
to explore causal relationships by using genetic variants
as proxies for modifiable risk factors, thereby minimizing confounding and reverse causation [11]. The adventof comprehensive genome-wide association studies(GWAS) has enhanced the feasibility of MR to investigate
GERD’s causal effects on cancer risk [12]. Despite theseadvancements, prior MR studies have primarily focusedon cancers localized to the gastrointestinal tract, without
thoroughly examining systemic cancers and the influenceof lifestyle factors such as smoking, alcohol consumption,body mass index (BMI), and major depression [13].
Our study aims to address these gaps by using MR to
explore the causal relationship between GERD and bothproximal and systemic cancer risks. Specifically, we
extend the investigation beyond proximal organ cancers
to include a broader range of systemic impacts, while
adjusting for lifestyle and mental health factors such as
smoking, alcohol use, BMI, and major depression. By
integrating data from multiple GWAS and employing
rigorous statistical methods, our study seeks to provide

a comprehensive understanding of the potential causal
links between GERD and various cancer types. Furthermore, our research highlights the importance of integrating GERD management into cancer prevention strategies.
By establishing a clearer causal relationship, our findings could influence future screening recommendations,guide lifestyle and dietary advice for GERD patients, andinform clinical practices regarding GERD managementwith an oncogenic perspective.

MethodStudy design and overview

In our study, we adopted a two-sample MR approach toelucidate the causal relationships between GERD andthe risk of various cancers. This investigation further
employed a multivariable MR technique to discern the
direct effects of GERD on cancer risk. We also identified a range of mediators that influence the connection
between GERD and cancer risk across different cancer
types. The comprehensive design of our research is illustrated in Fig. 1. Our analysis drew upon publicly available
summary statistics related to GERD, potential mediators,
and pan-cancer outcomes from previous publications andconsortia. As these primary studies had secured approval
from their respective Institutional Review Boards (IRBs),
our secondary analysis did not necessitate additional IRB
consent.
Data sources of exposure and outcome

The exposure dataset for GERD was developed by Ong
et al. [14]. This work implemented a multitrait GWAS
model that integrated GWAS for BMI, major depressive
disorder (MDD), educational attainment, GERD, andBarrett’s esophagus (BE) to unveil additional susceptibility loci for GERD. This comprehensive dataset included
129,080 cases and 473,524 controls of European ancestry,
directly retrieved from the GWAS Catalog (https://​www.​ebi.​ac.​uk/​gwas/​studi​es/​GCST9​00005​14). The outcome
datasets covered a wide array of cancers, including brain
cancer, thyroid cancer, oral cavity and pharyngeal cancer,
esophageal cancer, lung cancer, lung adenocarcinoma,lung squamous cell carcinoma, breast cancer, gastric cancer, cardia cancer, liver cancer, pancreatic cancer, coloncancer, colorectal cancer, prostate cancer, bladder cancer,
ovarian cancer, cervical cancer, and endometrial cancer.
These datasets were acquired from the UK Biobank anda variety of other GWAS consortia, including ILCCO,TRICL-UK, FinnGen, OncoArray Consortium, OCAC,

Wu et al. BMC Medicine(2024) 22:323

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Fig. 1 MR assumption and flow chart. A MR assumption: I, SNPs are not associated with confounder; II, SNPs are strongly associated with the GERD;
III, SNPs influence the cancer solely through the GERD. B Analysis flow chart

Schumacher FR et al., BCAC, and O’Mara TA et al.
Similarly, mediator variables were sourced from various
datasets provided by the GIANT Consortium, GSCAN
Consortium, Within-family GWAS Consortium, PGC
Consortium, and the GWAS and Sequencing Consortium of Alcohol and Nicotine use. For a comprehensive
overview of these data sources and their access links,
refer to Additional file 1: Table S1.

SNP selection

Our MR analysis aimed to investigate potential causal
connections between GERD and a spectrum of cancers
using genetic variants as instrumental variables (IVs). The
validity of an MR analysis rests on three critical assumptions: (1) IVs are not confounded by external factors; (2)there is a strong association between IVs and the exposure; and (3) IVs influence the outcome solely throughWu et al. BMC Medicine(2024) 22:323

the exposure [15]. Initially, we selected single nucleotide
polymorphisms (SNPs) exhibiting a genome-wide significant association (P < 5 × 10^−8) with the traits of interest as IVs. When necessary, we expanded our selection to
include SNPs with P values up to 5e−6 to ensure a robust
MR analysis. Linkage disequilibrium clumping was thenperformed to exclude closely linked SNPs (r^2 < 0.01,
window size > 10 MB) [16]. Palindromic SNPs with allele
frequencies near 0.5 were also excluded to synchronize
the exposure and outcome datasets. The list of selected
SNPs used in the study can be found in Additional file 1:
Table S2. The effectiveness of our genetic instruments
was validated by calculating the F statistic [17], ensuring
a minimal risk of weak instrument bias [18].
Statistical analysis

Our primary analysis was conducted using the inverse
variance-weighted (IVW) method [19], renowned for its
efficacy in establishing causal inferences. Supplemental
analyses included the weighted median approach [20]and MR-Egger regression [21] to account for potential pleiotropy. The MR-PRESSO test [22] was utilized
to detect pleiotropy and outliers, with Cochran’s Q test
assessing heterogeneity [23]. For significant heterogeneity, a random-effects IVW model was applied. To mitigate the risk of false discoveries due to multiple testing,
we employed the false discovery rate (FDR) [24] and Bonferroni correction [25]. Analyses were performed using
the two-sample MR, Mendelian randomization, and
MR-PRESSO packages in R (version 4.2.1). Mediation
analysis employed a two-step MR approach to evaluate
indirect effects, with mediation effect size and significance assessed via the product of coefficients method[26] and Sobel test [27].

Results
Causal effect analysis of GERD on site‑specific cancers

Our rigorous exploration of the causal effects of GERD
on the incidence of various cancers at specific sites integrated genetic data from extensive GWAS across multiple
databases, comprehensively assessing the links between
GERD and 19 different cancer sites. In our methodological approach, we utilized MR to infer causation using
genetic variations as instrumental variables, significantly
reducing the confounding often seen in observational
studies. The MR analysis unveiled associations between
GERD and various types of cancer, as itemized in Additional file 1: Table S3. To avoid the influence of SNP confounders, we used LD traits [28] to identify 63 uniquepotential confounding SNPs, as shown in Additional
file 1: Table S4. After removing these confounding SNPs,
we re-evaluated the association between GERD and various cancers across multiple databases using MR, retained

Page 4 of 13

the valid results, and conducted a meta-analysis on theseresults (Table 1). Post-application of false discovery rate(FDR) correction, the meta-analysis results indicated asignificant association between GERD and increased riskof various cancers (Fig. 2). Specifically, GERD was associated with higher incidence rates of lung cancer (OR =1.25, 95% CI: 1.18–1.32), lung adenocarcinoma (OR =1.15, 95% CI: 1.07–1.23), lung squamous carcinoma (OR= 1.32, 95% CI: 1.21–1.44), bladder cancer (OR = 1.22,
95% CI: 1.08–1.36), ovarian cancer (OR = 1.11, 95% CI:
1.03–1.20), and pancreatic cancer (OR = 1.42, 95% CI:
1.19–1.71). Additionally, results from individual datasets indicated significant associations between GERD
and cervical cancer in the FinnGen dataset (OR = 1.23,
95% CI: 1.06–1.42), esophageal cancer in the UK Biobank
dataset (OR = 1.93, 95% CI: 1.12–3.35), and oral andpharyngeal cancer in the Lesseur dataset (OR = 1.51,
95% CI: 1.18–1.93). There was no significant association
between GERD and other types of cancer.
The robustness of these findings was further validated by supplementary analyses using the weighted
median (WM) and MR-Egger methods (Additional file 1:
Table S5), despite some outcomes showing broad confidence intervals. The MR-PRESSO analysis (Additional
file 1: Table S6) identified outliers in the datasets for lungand ovarian cancers. However, even with outlier exclusion, the associations between GERD and cancer risk
retained significance. Additionally, in reverse MR analysis, we did not find a significant effect of cancer on GERD
(Additional file 1: Table S7). These findings strengthen
the evidence for GERD’s role in cancer etiology andunderscore the need for focused prevention strategies
targeting GERD.
Multivariable MR analysis

Recognizing that smoking, alcohol consumption, obesity,and major depressive disorder are established risk factors
for various cancers, we conducted a multivariable MR
study to systematically mitigate these confounding effects.
Our objective was to refine the direct causal relationshipbetween GERD and overall cancer risk. Significant findings from our database were analyzed (Additional file 1:
Table 8) and followed by a comprehensive meta-analysis(Table 2). Our results indicate substantial variation in theassociation between GERD and various cancer types when
adjusting for individual or combined factors. Specifically,
the link between GERD and cervical cancer was significantly influenced by adjustments for smoking habits. No
significant correlation was found between GERD and theincidence of bladder or ovarian cancer after adjusting for
BMI. The weekly amount of alcohol consumption did notalter the relationship between GERD and the cancer types
studied. After adjusting for major depressive disorder, noWu et al. BMC Medicine(2024) 22:323

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Table 1 MR analysis of GERD association with multiple cancer risks
OutcomeNumber of SNPs

OR(95% CI)

P val

Brain cancer (FinnGen)

196

0.95(0.72–1.26)

0.742

Brain cancer (UK Biobank)199

1.14(0.81–1.61)

0.449

1.03(0.82–1.27)

0.824

0.95(0.77–1.16)

0.583

Meta (Q_Pval = 0.426, I^2 = 0%)
Thyroid cancer (FinnGen)

196

Thyroid cancer (UK Biobank)

199

Meta (Q_Pval = 0.116, I^2 = 60%)

1.3(0.92–1.83)

0.133

1.07(0.79–1.46)

0.646

FDR

Bonferroni

8.73E−01

1.00E+00

0.776

1.00E+00

Oral cavity and pharyngeal cancer (Lesseur)170

1.51(1.18–1.93)

0.001

2.86E−03

1.61E−02

Esophageal cancer (UK Biobank)199

1.93(1.12–3.35)

0.019

3.75E−02

3.37E−01

Lung cancer (UK Biobank)199

1.58(1.14–2.21)

0.007

2.09E−13

2.09E−13

9.15E−04

3.66E−03

1.30E−09

2.59E−09

8.84E−01

1.00E+00

Lung cancer (ILCCO)

192

1.27(1.14–1.41)<0.001Lung cancer (TRICL)

198

1.24(1.15–1.34)<0.001Lung cancer (FinnGen)

196

Meta (Q_Pval = 0.458, I^2 = 0%)Lung cancer (adenocarcinoma_FinnGen)

196

1.18(1.03–1.36)

0.019

1.25(1.18–1.32)<0.0011.19(0.95–1.49)

0.123

Lung cancer (adenocarcinoma_ILCCO)

192

1.12(0.96–1.3)

0.147

Lung cancer (adenocarcinoma_TRICL)

199

1.15(1.05–1.26)

0.002

1.15(1.07–1.23)<0.0011.2(0.93–1.54)

0.152

Meta (Q_Pval = 0.892, I^2 = 0%)Lung cancer (squamous_FinnGen)

196

Lung cancer (squamous_ILCCO)

192

1.32(1.14–1.54)<0.001Lung cancer (squamous_TRICL)

199

1.35(1.2–1.51)<0.0011.32(1.21–1.44)<0.0011.01(0.96–1.07)

0.676

Meta (Q_Pval = 0.719, I^2 = 0%)
Breast cancer (BCAC)

190

Breast cancer (FinnGen)

196

0.97(0.9–1.04)

0.428

Breast cancer (UK Biobank)199

0.94(0.56–1.6)

0.824

1.00(0.96–1.04)

0.884

1.08(0.87–1.36)

0.478

Meta (Q_Pval = 0.660, I^2 = 0%)
Gastric cancer (FinnGen)

196

Gastric cancer (UK Biobank)

199

Meta (Q_Pval = 0.200, I^2 = 39%)1.4(1.02–1.94)

0.04

1.18(0.98–1.42)

0.079

1.19E−01

1.00E+00

8.15E−01

1.00E+00

9.06E−04

2.72E−03

4.16E−01

1.00E+00

6.72E−02

7.39E−01

6.72E−02

6.72E−01

2.86E−03

1.71E−02

Cardia cancer (UK Biobank)199

1.11(0.63–1.93)

0.725

Pancreatic cancer (FinnGen)

196

1.43(1.15–1.79)

0.002

Pancreatic cancer (UK Biobank)

199

Meta (Q_Pval = 0.905, I^2 = 0%)
Colon cancer (FinnGen)

196

Colon cancer (UK Biobank)

199

Meta (Q_Pval = 0.030, I^2 = 79%)
Colorectal cancer (FinnGen).gz

196

Colorectal cancer (UK Biobank)

199

Meta (Q_Pval = 0.595, I^2 = 0%)
Prostate cancer (FinnGen)

196

1.4(1.02–1.92)

0.038

1.42(1.19–1.71)<0.0010.81(0.71–0.91)

0.001

1(0.86–1.16)

0.998

0.89(0.72–1.10)

0.301

0.89(0.8–0.99)

0.035

0.97(0.72–1.32)

0.854

0.90(0.81–1.00)

0.041

1.02(0.94–1.11)

0.587

Prostate cancer (UK Biobank)199

0.96(0.88–1.06)

0.435

Prostate cancer (Schumacher FR)

197

0.94(0.89–0.98)

0.01

0.96(0.92–1.00)

0.037

1.19(1.01–1.41)

0.034

Meta (Q_Pval = 0.193, I^2 = 39%)
Bladder cancer (FinnGen)

196

Bladder cancer (UK Biobank)

199

Meta (Q_Pval = 0.776, I^2 = 0%)
Ovarian cancer (FinnGen)

196

1.24(1.05–1.45)

0.011

1.22(1.08–1.36)

0.001

1.07(0.86–1.33)

0.556

Ovarian cancer (UK Biobank)199

1.17(0.91–1.51)

0.21

Ovarian cancer (OCAC)

190

1.11(1.02–1.21)

0.021

Meta (Q_Pval = 0.860, I^2 = 0%)1.11(1.03–1.20)

0.009

1.91E−02

1.53E−01

Cervical cancer (FinnGen)

196

1.23(1.06–1.42)

0.006

1.43E−02

9.99E−02

Endometrial cancer (O’Mara TA)

199

1.19(1.09–1.29)<0.001

Endometrial cancer (UK Biobank)

199

7.76E−01

1.00E+00

Meta (Q_Pval = 0.048, I^2 = 74%)

0.91(0.7–1.17)

0.443

1.07(0.82–1.38)

0.632

FDR: method to correct P values for multiple comparisons; Bonferroni: adjusts P values for multiple comparisons to ensure stricter significanceWu et al. BMC Medicine(2024) 22:323

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Fig. 2 Simplified schematics of GERD’s effects on various cancers

significant association was observed between GERD andeither bladder or cervical cancer.
Even after adjusting for these confounding factors, significant associations between GERD and certain specific cancers (lung cancer, including adenocarcinoma and squamouscell carcinoma, oral cavity, pharyngeal cancer, and esophageal cancer) remained. Notably, most odds ratios (ORs)
increased. For instance, the OR for lung cancer increased
from 1.25 (95% CI: 1.18–1.32) to 1.34 (95% CI: 1.26–1.42)
after adjusting for BMI, to 1.29 (95% CI: 1.23–1.36) after

adjusting for alcohol intake, and to 1.34 (95% CI: 1.24–1.44)
after adjusting for major depressive disorder. Similarly,
the OR for lung adenocarcinoma rose from 1.15 (95% CI:
1.07–1.23) to 1.24 (95% CI: 1.12–1.37) after adjusting for
BMI and to 1.21 (95% CI: 1.07–1.37) after adjusting for
major depressive disorder. The OR for lung squamous cell
carcinoma increased from 1.32 (95% CI: 1.21–1.44) to 1.43
(95% CI: 1.30–1.57) after adjusting for BMI, to 1.41 (95%
CI: 1.30–1.53) after adjusting for alcohol intake, and to 1.56
(95% CI: 1.38–1.77) after adjusting for major depressive

2.16(1.23–3.79) 0.007204945 1.70(1.05–2.75) 0.03103533

1.22(1.01–1.48) 0.037609315 1.39(1.20–1.62) 2.07E−05

Pancreatic cancer

1.30(1.19–1.43) 1.29E−08

1.35(1.19–1.53) 3.76E−06

1.46(1.16–1.83) 0.001032751 1.47(1.23–1.76) 1.67E−05

1.04(0.81–1.33) 0.759557172

1.18(1.06–1.31) 0.002663911 1.10(1.01–1.18) 0.019268421 1.06(0.95–1.18) 0.331160306

1.46(1.05–2.03) 0.024816359 1.34(1.03–1.73) 0.027299163 1.73(1.22–2.44) 0.00191425

2.13(1.08–4.22) 0.029864474 1.93(1.10–3.36) 0.020939446 2.57(1.23–5.37) 0.012027574

1.56(1.38–1.77) 9.24E−13

OR(95% CI) represents the GERD’s meta effect and confidence interval on cancer after adjusting risk factor. P value represents the significance of meta effect1.07(0.99–1.17) 0.105112831 1.11(1.03–1.19) 0.00442558

1.56(1.25–1.94) 7.13E−05

1.41(1.30–1.53) 1.32E−16

Ovarian cancer

Oral cavity and pharyngeal cancer 1.90(1.46–2.47) 1.43E−06

1.43(1.30–1.57) 2.04E−13

1.23(1.14–1.33) 9.27E−08

Esophageal cancer

1.20(1.13–1.27) 1.29E−10

Lung cancer (squamous)

1.34(1.24–1.44) 1.46E−13

1.18(1.08–1.29) 0.000163614 1.21(1.07–1.37) 0.003046497 1.15(1.06–1.24) 0.000978048 1.18(1.03–1.36) 0.014669644

1.29(1.23–1.36) 9.60E−23

1.24(1.12–1.37) 4.54E−05

Pval

1.34(1.26–1.42) 4.80E−23

OR(95% CI)

Lung cancer (adenocarcinoma)

Pval

Lung cancer

OR(95% CI)

1.15(0.98–1.34) 0.081850817 1.19(1.06–1.33) 0.002374946 1.16(0.92–1.47) 0.216387267

Pval

Adjust All

1.21(1.03–1.42) 0.020287784 1.23(1.07–1.40) 0.002523341 1.17(0.94–1.44) 0.152073528 1.15(0.98–1.35) 0.088628315 1.22(0.99–1.51) 0.063601433

OR(95% CI)

Adjust smoking

1.18(0.93–1.49) 0.165518502 1.23(1.12–1.36) 2.99E−05

Pval

Adjust major depression

Cervical cancer

OR(95% CI)

OR(95% CI)

Pval

Adjust drinks

Adjust BMI

Bladder cancer

OutcomeTable 2 MR analysis between GERD and cancers adjusted for risk factors

Wu et al. BMC Medicine(2024) 22:323
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Wu et al. BMC Medicine(2024) 22:323

disorder. For esophageal cancer, the OR increased from1.93 (95% CI: 1.10–3.35) to 2.16 (95% CI: 1.23–3.79) after
adjusting for BMI and to 2.13 (95% CI: 1.08–4.22) after
adjusting for major depressive disorder. The OR for oralcavity and pharyngeal cancer increased from 1.51 (95%
CI: 1.18–1.93) to 1.90 (95% CI: 1.46–2.47) after adjustingfor BMI and to 1.56 (95% CI: 1.25–1.94) after adjusting foralcohol intake. When all confounding factors were adjusted
simultaneously, these associations remained significant,and most risks even increased. For example, the adjusted
odds ratio (OR) for lung cancer was 1.23 (95% CI: 1.14–1.33), for lung adenocarcinoma was 1.18 (95% CI: 1.03–
1.36), and for lung squamous cell carcinoma was 1.35 (95%
CI: 1.19–1.53). The OR for oral cavity and pharyngeal cancer was 1.73 (95% CI: 1.22–2.44), and particularly noteworthy, the OR for esophageal cancer increased to 2.57 (95%
CI: 1.23–5.37). These results underscore the robustness ofthese associations, indicating that GERD is a significant risk
factor for these cancers.
Mediation effects of GERD between lifestyle and mental
health factors and various types of cancers

In our mediation analysis, we aimed to determine whether
GERD serves as a mediating factor in the relationshipFig. 3 Mendelian analysis between the GERD and mediator

Page 8 of 13

between lifestyle and mental health factors and the riskof various cancers. Preliminary assessments evaluated thepotential impact of these factors on GERD. The results of
the Mendelian randomization analysis (Fig. 3) revealed
significant associations between BMI, major depression,and smoking behavior with GERD. Specifically, BMI was
significantly associated with GERD, with an OR of 1.68
(95% CI: 1.51–1.87), indicating that higher BMI substantially increases the likelihood of GERD. Similarly, major
depression showed a significant relationship with GERD
(OR = 1.84, 95% CI: 1.68–2.01), suggesting that individuals with severe depression are more prone to experiencing
GERD. Additionally, smoking behavior was significantly
associated with GERD (OR = 1.44, 95% CI: 1.31–1.58),
indicating that smoking similarly elevates the risk of
GERD. Further analysis using Mendelian randomization
explored the relationships between BMI, major depression, and smoking behavior with various cancers (Additional file 1: Table S9). The results indicate that major
depression is associated with an increased incidence of
bladder cancer, and BMI is linked to multiple cancers,
including various forms of lung cancer, bladder cancer,
esophageal cancer, and pancreatic cancer. Additionally,smoking behavior is associated not only with an increased

Wu et al. BMC Medicine(2024) 22:323

Page 9 of 13

incidence of various forms of lung cancer but also withoral cancer, pharyngeal cancer, and ovarian cancer.
Table 3 and Additional file 1: Table S10 highlight themediating roles of GERD between various exposure factors and different cancer outcomes. The analysis foundthat GERD mediates 28.54% of the association between
severe depression and bladder cancer, underscoring asignificant intermediary role of GERD. Furthermore,
GERD notably mediates the relationship between
BMI and various cancers, particularly in lung cancer(60.16%), lung squamous cancer (average 42.85%), andbladder cancer (44.48%). GERD also significantly mediates the impact of smoking behavior on various cancers,
including lung cancer (17.98%), lung adenocarcinoma(13.60%), lung squamous cancer (12.87%), oral cancer and pharyngeal cancer (33.59%), and esophageal
cancer (24.17%). These findings emphasize the complex intermediary role of GERD in the interactions
between lifestyle and mental health factors and cancer
risk, highlighting GERD as a significant factor in cancer
prevention strategies. The observed mediation effects
underscore GERD as an important risk factor for specific cancers and suggest that addressing GERD could
be a beneficial component of comprehensive cancer
prevention and monitoring protocols.

Discussion
The role of GERD in the development of various cancers has been increasingly recognized, although directcausal relationships have yet to be definitively established[1, 2]. In this study, we employed MR to investigate thepotential causal relationships between GERD and various
cancer types. Our findings indicate a significant positive
correlation between GERD and the risk of several cancers, including overall lung cancer, lung adenocarcinoma,lung squamous cell carcinoma, esophageal cancer, oralcavity, pharyngeal cancer, pancreatic cancer, bladder cancer, cervical cancer, and ovarian cancer.

Specifically, GERD is associated with an increased riskof lung, oral, throat, and esophageal cancers [3–7]. Theseobservations are consistent with prior epidemiologicalstudies suggesting that the harmful effects of stomach
acids and bile, which are components of gastric contents, on various tissues could be a potential mechanism[29]. A meta-analysis revealed that individuals experiencing GERD symptoms at least weekly have nearly afivefold increased risk of developing esophageal adenocarcinoma. Furthermore, for those with daily symptoms,
this risk escalates to a sevenfold increase [3]. While ourstudy confirms a significant association between GERD
and increased cancer risks, elucidating the biologicalmechanisms underlying these relationships is essential.
Chronic exposure to stomach acid and bile, which iscommon in GERD, can lead to continuous inflammationand cellular damage in the esophagus and other tissues,potentially resulting in carcinogenesis. For instance, thereflux of gastric contents into the esophagus can induce
Barrett’s esophagus, a precursor to esophageal adenocarcinoma, through repeated cycles of injury and repair
causing cellular changes [30, 31]. Additionally, the aspiration of acidic gastric contents into the lungs mightlead to chronic inflammation and an increased risk oflung cancer, a hypothesis supported by multiple studies.
Chronic inflammation in lung tissues caused by persistent exposure to gastric acid can lead to DNA damage
and promote carcinogenesis. This association has been
corroborated by numerous studies, collectively indicating an increased risk of lung cancer among individuals
with frequent GERD symptoms [32–34]. Despite variations in methodologies and patient populations, thesestudies consistently demonstrate a positive correlation,suggesting that GERD may contribute to lung cancer
development. Furthermore, substantial cross-disciplinary research has consistently established a significant
relationship between GERD and increased risks of oral
and throat cancers. Extensive research over many years,

Table 3 Mediation proportion of GERD
ExposureMediator

OutcomeMediation
proportion

Major depression

GERD

Bladder cancer

28.54%

Body mass index

GERD

Bladder cancer

44.48%

Body mass index

GERD

Lung cancer

60.16%

Body mass index

GERD

Lung squamous cancer

42.85%

Smoking initiation

GERD

Lung cancer

17.98%

Smoking initiation

GERD

Lung adenocarcinoma

13.60%

Smoking initiation

GERD

Lung squamous cancer

12.87%

Smoking initiation

GERD

Oral cavity and pharyngeal cancer

33.59%

Smoking initiation

GERD

Esophageal cancer

24.17%

Wu et al. BMC Medicine(2024) 22:323

including case-control studies, cohort studies, and systematic reviews, suggests that chronic exposure to stomach acid and other refluxates due to GERD may cause
inflammation and tissue damage in the oral and throat
regions, thereby increasing cancer risk. These findings
affirm that GERD may indeed be a contributory factor
in the development of these types of cancers [4, 35–37].
Notably, our study employed both MR analysis and multivariable MR analysis to provide robust evidence of thecorrelation between GERD and the increased risk oflung, oral, throat, and esophageal cancers. The multivariable MR analysis, which adjusts for confounding factors
such as BMI, smoking, alcohol consumption, and major
depressive disorder, further strengthens the robustnessof our findings. For instance, after adjusting for BMI, theORs for various cancers, including lung cancer, increased
significantly, highlighting the persistent association evenafter controlling for major confounders. Moreover, theOR for esophageal cancer increased substantially after
adjusting for all confounding factors, underscoring thesignificant risk posed by GERD. These results emphasize
the critical role of GERD as a significant risk factor forthese cancers and highlight the need to include GERD
management in cancer prevention strategies.
Currently, there is insufficient scientific evidence todirectly support the correlation between GERD and therisks of pancreatic, bladder, cervical, and ovarian cancers.
However, several studies have preliminarily explored thepotential links between GERD and these cancers. For
example, Heather Katz and colleagues reported a patientwith a history of GERD who was diagnosed with esophageal adenocarcinoma at the age of 49. Shortly thereafter, metastatic lesions were discovered in her bladder.
Notably, immunohistochemical staining of her bladdertumor was consistent with metastatic esophageal cancer, although clinical cases of esophageal adenocarcinoma metastasizing to the bladder are extremely rare[38]. On the other hand, Ati Burassakarn and colleagues
found a significant association between a history of
GERD and the prevalence of HPV infection. Given that
HPV infection is widely recognized as a major risk factor for cervical cancer, this finding provides further clues
for exploring the relationship between GERD and cervical cancer risk [39]. Additionally, Dana Meredith Chaseand colleagues found that women diagnosed with ovarian cancer experienced symptoms of heartburn and acidreflux several months before diagnosis [40]. A study by
Julia Hippisley-Cox also indicated that heartburn is independently associated with an increased risk of pancreatic cancer, with women experiencing heartburn having
a 2.5-fold increased risk of developing pancreatic cancer[41]. Although the specific mechanisms by which GERD
may increase the risks of these cancers remain unclear,

Page 10 of 13

the aforementioned studies and our current findings
provide important theoretical foundations and research
directions for future investigations into the relationshipbetween GERD and increased cancer risks. These relationships likely involve complex biological mechanisms
and multiple risk factors, necessitating further prospective studies and large cohort studies to validate and elucidate them.
Our mediation analysis suggests that GERD may serveas an important mediator in the relationships between
BMI, major depression, smoking, and various cancers.
The relationship between BMI and GERD has been
extensively studied. A high BMI increases abdominalpressure, promoting the reflux of stomach contents
into the esophagus, thereby leading to GERD [42, 43].
The relationship between major depression and GERD
has also been thoroughly investigated. Patients withdepression often experience gastrointestinal symptoms,
including GERD [44]. Studies indicate that depression
might increase the risk of GERD by altering gastrointestinal function and affecting appetite and dietary habits[45–47]. Smoking is a known risk factor for GERD, as it
can lower the pressure of the lower esophageal sphincter
and increase gastric acid secretion, thus facilitating acidreflux [48–50]. Therefore, smoking, major depression,and high BMI are more likely to lead to GERD, and our
research indicates that GERD is a risk factor for bladder cancer, cervical cancer, lung cancer, lung adenocarcinoma, lung squamous cancer, esophageal cancer, oral
cancer, pharyngeal cancer, ovarian cancer, and pancreatic cancer. Thus, GERD may act as a mediating variable,
linking BMI, severe depression, and smoking with theincidence of various cancers. This complex intermediaryrole underscores the pivotal position of GERD in linking lifestyle and mental health factors with the risk ofvarious cancers. Through its significant mediating effect,
GERD reveals the potential mechanisms between thesefactors and cancer occurrence, elucidating how lifestyle
habits and psychological states can influence the development of GERD, thereby increasing or reducing therisk of specific cancers. These findings not only help us
to understand more deeply the biological basis of theseassociations but also may provide important guidance
for the formulation of prevention and treatment strategies. By integrating strategies aimed at optimizing lifestyle and mental health, we cannot only enhance themanagement of gastroesophageal reflux disease but also
potentially reduce the associated cancer risks.
The investigation employed various sensitivity analyses to enhance the credibility of the conclusions. The
consistency among the majority of WM, MR-Egger, andIVW methods further validated the robustness of thestudy results. Although some outcomes exhibited wideWu et al. BMC Medicine(2024) 22:323

confidence intervals, the overall trend of the associations remained stable. Additionally, the application of
the MR-PRESSO method helped identify and eliminate
potential outliers, thereby increasing the reliability of
the conclusions. Since both the exposure and outcome
groups were predominantly of European descent, thelikelihood of bias due to population stratification was
significantly reduced. Nevertheless, several limitations
should be noted. The reliance on genetic data may
not fully capture the complexity of the relationshipbetween GERD and cancer risk. Furthermore, the findings, being based primarily on a population of European ancestry, may not be directly applicable to otherpopulations. Although various potential confounders
were considered, not all possible factors that might
influence the observed associations were included.
Additionally, the study did not differentiate between
different phenotypes of GERD (such as erosive andnon-erosive reflux disease), and varying severity may
have different impacts on cancer risk. Future researchshould explore these aspects to better understand therole of GERD in cancer development. Despite theselimitations, the study provides valuable insights into
the potential causal relationship between GERD andthe risk of various cancers.

Conclusions
This study provides compelling evidence, significantly
revealing a close association between GERD and various types of cancer. This finding further strengthens
the notion of considering GERD as an important risk
factor in the development of cancer, emphasizing thenecessity of incorporating it into comprehensive cancer
prevention strategies. Furthermore, this study identifies
the critical roles that lifestyle and mental health factors play in regulating the association between GERD
and cancer. This presents a novel perspective for future
in-depth exploration of this relationship and the development of potential intervention strategies. Based onthese findings, future research can further unveil thepotential mechanisms underlying the increased cancer risk associated with GERD. A more comprehensive
understanding of the mediating roles of BMI, severe
depression, and smoking in the relationship between
GERD and cancer is especially needed. With the interplay of these variables, clinicians can more accurately
predict cancer risk, thereby designing more personalized prevention strategies for patients with GERD.
Abbreviations
GERD	Gastroesophageal reflux disease
GWAS	Genome-wide association studies
MR	Mendelian randomization
OR	Odds ratio

Page 11 of 13

CI	Confidence interval
BMI	Body mass index
FDR	False discovery rate
IVW	Inverse variance weighted
WM	Weighted medianIVs	Instrumental variables
SNPs	Single nucleotide polymorphisms
MR-PRESSO	Mendelian Randomization Pleiotropy RESidual Sum and Outlier
TRICL	Transdisciplinary Research in Cancer of the Lung
ILCCO	International Lung Cancer Consortium
IRB	Institutional Review Board
BE	Barrett’s esophagus
MDD	Major depressive disorder

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03526-5.
Additional file 1: Table S1. Overview of data. Table S2. All-selected SNPs in
the study. Table S3. Mendelian randomization analysis of GERD association with pan-cancer risk. Table S4. 63 unique potential confounding
SNPs. Table S5. Sensitivity analysis for GERD and cancer. Table S6. Outlier
analysis and correction of SNPs. Table S7. Reverse MR analysis of cancer on
GERD. Table S8. Comparison of effects before and after adjusting variables.
Table S9. Mendelian randomization analysis of the major depression, BMI,
and smoking initiation association with pan-cancer risk. Table S10. Resultsfrom a two-step Mendelian randomization mediation analysis.
Acknowledgements
We appreciate all authors who participated in this study. Additionally, we are
grateful to the MiBioGen consortium and Open GWAS for providing the GWAS
summary statistics.
Authors’ contributions
GW and LC2 drafted the manuscript, GW, YL, and DN performed statisticalanalysis and technical support. MZ, XL, LC1, QH, and YL acquired the data. GWand LC2 revised and finalized the manuscript. YH made significant revisions to
the manuscript and ultimately approved it for publication. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Outstanding Resident Clinical Postdoctoral
Program of Zhongshan Hospital affiliated with Fudan University and the China
Postdoctoral Science Foundation (Certificate Number: 2023M730674).
Availability of data and materials
No datasets were generated or analysed during the current study.

Declarations
Ethics approval and consent to participate
We relied on publicly accessible summary statistics pertaining to GERD,
mediators, and pan-cancer, sourced from earlier publications or consortiums.
Given that these original studies had already received approval from theirrespective Institutional Review Boards (IRBs), no additional IRB approval was
required for our study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Author details
1
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University,
Shanghai 200032, China. 2 Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China. 3 Regenerative
Medicine Institute, School of Medicine, National University of Ireland (NUI),

Wu et al. BMC Medicine(2024) 22:323

Galway, Ireland. 4 Department of Physiology, School of Medicine, National University of Ireland (NUI), Galway, Ireland. 5 Department of Laboratory Medicine,
Huashan Hospital, Fudan University, Shanghai, China. 6 Department of Radiology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan
University, Shanghai, China.
Received: 8 March 2024 Accepted: 10 July 2024

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